Early COPD Research Articles

Alpha-1-antitrypsin-deficiency is associated with lower cardiovascular risk: an approach based on federated learning

BackgroundChronic obstructive pulmonary disease (COPD) is an inflammatory multisystemic disease caused by environmental exposures and/or genetic factors. Inherited alpha-1-antitrypsin deficiency (AATD) is one of the best recognized genetic factors increasing the risk for an early onset COPD with emphysema. The aim of this study was to gain a better understanding of the associations between comorbidities and specific biomarkers in COPD patients with and without AATD to enable future investigations aimed, for example, at identifying risk factors or improving care.MethodsWe focused on cardiovascular comorbidities, blood high sensitivity troponin (hs-troponin) and lipid profiles in COPD patients with and without AATD. We used clinical data from six German University Medical Centres of the MIRACUM (Medical Informatics Initiative in Research and Medicine) consortium. The codes for the international classification of diseases (ICD) were used for COPD as a main diagnosis and for comorbidities and blood laboratory data were obtained. Data analyses were based on the DataSHIELD framework.ResultsOut of 112,852 visits complete information was available for 43,057 COPD patients. According to our findings, 746 patients with AATD (1.73%) showed significantly lower total blood cholesterol levels and less cardiovascular comorbidities than non-AATD COPD patients. Moreover, after adjusting for the confounder factors, such as age, gender, and nicotine abuse, we confirmed that hs-troponin is a suitable predictor of overall mortality in COPD patients. The comorbidities associated with AATD in the current study differ from other studies, which may reflect geographic and population-based differences as well as the heterogeneous characteristics of AATD.ConclusionThe concept of MIRACUM is suitable for the analysis of a large healthcare database. This study provided evidence that COPD patients with AATD have a lower cardiovascular risk and revealed that hs-troponin is a predictor for hospital mortality in individuals with COPD.

Integrating Artificial Intelligence in the Diagnosis of COPD Globally: A Way Forward.

The advancement of artificial intelligence (AI) capabilities has paved the way for a new frontier in medicine, which has the capability to reduce the burden of COPD globally. AI may reduce health care-associated expenses while potentially increasing diagnostic specificity, improving access to early COPD diagnosis, and monitoring COPD progression and subsequent disease management. We evaluated how AI can be integrated into COPD diagnosing globally and leveraged in resource-constrained settings.AI has been explored in diagnosing and phenotyping COPD through auscultation, pulmonary function testing, and imaging. Clinician collaboration with AI has increased the performance of COPD diagnosing and highlights the important role of clinical decision-making in AI integration. Likewise, AI analysis of computer tomography (CT) imaging in large population-based cohorts has increased diagnostic ability, severity classification, and prediction of outcomes related to COPD. Moreover, a multimodality approach with CT imaging, demographic data, and spirometry has been shown to improve machine learning predictions of the progression to COPD compared to each modality alone. Prior research has primarily been conducted in high-income country settings, which may lack generalization to a global population. AI is a World Health Organization priority with the potential to reduce health care barriers in low- and middle-income countries. We recommend a collaboration between clinicians and an AI-supported multimodal approach to COPD diagnosis as a step towards achieving this goal. We believe the interplay of CT imaging, spirometry, biomarkers, and sputum analysis may provide unique insights across settings that could provide a basis for clinical decision-making that includes early intervention for those diagnosed with COPD.

COPD With Lung Cancer Among Older United States Adults: Prevalence, Diagnostic Timeliness, and Association With Earlier Stage Tumors.

Chronic obstructive pulmonary disease (COPD) is a common comorbidity among patients with lung cancer, and an important determinant of their outcomes, however, it is commonly underdiagnosed. Our objective was to estimate the prevalence of COPD among a cohort of U.S. lung cancer patients, the timing of a COPD diagnosis relative to their lung cancer diagnosis, and the association between an earlier diagnosis of COPD and stage of lung cancer, with consideration of patient sociodemographic modifying factors. We conducted an analysis of the Medicare-linked Surveillance, Epidemiology, and End Results database including patients aged 68+ years who were diagnosed with lung cancer between 2008 to 2017. Exposure: Prevalence of COPD was identified using claims and subclassified based on the timing of its diagnosis relative to the lung cancer diagnostic episode-"preexisting" if diagnosed > 3 months before lung cancer, and "concurrent" if diagnosed around the same time as the lung cancer (+/-3 months). Outcome: The stage of cancer at diagnosis (early versus late) was the outcome. Among 159,542 patients with lung cancer, 73.5% had COPD. Among those with COPD, 34.4% were diagnosed within 3 months of their lung cancer diagnosis and considered to have "concurrent COPD." We observed a positive association between preexisting COPD diagnosis and early-stage lung cancer (prevalence ratio= 1.27; 95% confidence interval= 1.23-1.30), in adjusted models which were stronger for male, non-Hispanic Black, and Hispanic patients. Seven out of 10 patients with lung cancer have COPD, however, many do not receive their COPD diagnosis until around the time of their lung cancer diagnosis. Among these patients, an early COPD diagnosis may improve early detection of lung cancer.

Endothelial to mesenchymal transition is an active process in smokers and patients with early COPD contributing to pulmonary arterial pathology.

We have previously reported pulmonary arterial remodelling in smokers and patients with early COPD, which can be attributed to endothelial to mesenchymal transition (EndMT). In this study, we aimed to evaluate if EndMT is an active mechanism in smokers and COPD. Immunohistochemical staining for the EndMT biomarkers CD31, N-cadherin, vimentin and S100A4 was done on lung resection tissue from 49 subjects. These comprised 15 nonsmoker controls (NC), six normal lung function smokers (NLFS), nine patients with small airway disease (SAD), nine current smokers with mild-moderate COPD (COPD-CS) and 10 ex-smokers with COPD (COPD-ES). Pulmonary arteries were analysed using Image ProPlus software v7.0. We noted reduced junctional CD31+ endothelial cells (p<0.05) in the intimal layer of all smoking groups compared to NC. We also observed increased abundance of the mesenchymal markers N-cadherin (p<0.05) and vimentin (p<0.001) in all smoking groups and across all arterial sizes versus NC, except for N-cadherin in large arteries in COPD-CS. The abundance of S100A4 correlated with arterial thickness (small: r=0.29, p=0.05; medium: r=0.33, p=0.03; large: r=0.35, p=0.02). Vimentin in the small arterial wall negatively correlated with forced expiratory volume in 1 s/forced vital capacity (r= -0.35, p=0.02) and forced expiratory flow rate at 25-75% of forced vital capacity (r= -0.34, p=0.03), while increased cytoplasmic CD31 abundance in the intimal layer of medium and large arteries negatively correlated with predicted diffusing capacity of the lung for carbon monoxide (medium: r= -0.35, p=0.04; large: r= -0.39, p=0.03). This is the first study showing the acquisition of mesenchymal traits by pulmonary endothelial cells from NLFS, SAD and mild-moderate COPD patients through EndMT. This informs on the potential early origins of pulmonary hypertension in smokers and patients with early COPD.

Epithelial-mesenchymal transition changes in nonsmall cell lung cancer patients with early COPD.

Epithelial-mesenchymal transition (EMT) might be central to lung cancer development in smokers and COPD. We illustrate EMT changes in a broader demographic of patient groups who were diagnosed with nonsmall cell lung cancer (adenocarcinoma and squamous cell carcinoma). These included COPD current and ex-smokers, patients with small airway disease and normal lung function smokers compared to normal controls. We had access to surgically resected small airway tissue from 46 subjects and assessed for airway wall thickness and immunohistochemically for the EMT biomarkers E-cadherin, N-cadherin, S100A4, vimentin and epidermal growth factor receptor (EGFR). All tissue analysis was done with a computer and microscope-assisted Image-Pro Plus 7.0 software. Airway wall thickness significantly increased across all pathological groups (p<0.05) compared to normal controls. Small airway epithelial E-cadherin expression markedly decreased (p<0.01), and increases in N-cadherin, vimentin, S100A4 and EGFR expression were observed in all pathological groups compared to normal controls (p<0.01). Vimentin-positive cells in the reticular basement membrane, lamina propria and adventitia showed a similar trend to epithelium across all pathological groups (p<0.05); however, such changes were only observed in reticular basement membrane for S100A4 (p<0.05). Vimentin was higher in adenocarcinoma versus squamous cell carcinoma; in contrast, S100A4 was higher in the squamous cell carcinoma group. EGFR and N-cadherin expression in both phenotypes was markedly higher than E-cadherin, vimentin and S100A4 (p<0.0001). EMT is an active process in the small airway of smokers and COPD diagnosed with nonsmall cell lung cancer, contributing to small airway remodelling and cancer development as seen in these patients.

Deep Learning Model for Early Subsequent COPD Exacerbation Prediction

Deep Learning Model for Early Subsequent COPD Exacerbation Prediction

Metabolic syndrome (mets) as one of the major comorbidities of chronic obstructive pulmonary disease (copd)

Aim: We aimed to investigate the association between COPD and MetS, the relation to the severity of airflow limitation. Methods: This is a cross-sectional study including 220 patients with initially diagnosed COPD (IG), aged 40 to 75 years and 58 non-COPD subjects matched by age, smoking status, body mass index, as controls (CG). All study participants underwent anthropometric measurements, fasting blood sugar (FBS), lipid profile, pulmonary evaluation (dyspnea severity assessment, baseline and postbronchodilator spirometry, gas analyses, chest X-ray). Results: Results presented statistically significant difference in presence of MetS in COPD patients compared to controls (32.27% vs 10.34%; P=0.0009). According to the GOLD classification, the frequencies of MetS in COPD patients were categorized in stages I, II, III, IV (17.54%, 37.10%, 34.62%, 40.82%, respectively). The proportion of patients with increased glycemic values was: a) GOLD1 - 18 (31.58%); b) GOLD 2 - 32 (51.61%); c) GOLD3 - 29 (55.77%); and d) GOLD4 - 31 (63.27%). There was no significant difference between IG and CG patients regarding HDL level. According to arterial hypertension the highest proportion was observed in GOLD3 - 22 (42.31%) followed by GOLD4 - 20 (40.82%), and GOLD3 - 22 (35.48 %), smallest in GOLD1 - 17 (29.82%). Conclusion: We found higher prevalence of MetS in patients with COPD even in early COPD stages compared to non-COPD. Our findings suggest an urgent need to develop comprehensive strategies for prevention, screening and start of treatment in early stage.

Understanding Early COPD.

Whereas COPD is currently defined as the presence of spirometric obstruction, the pathologic changes in individuals at risk including chronic mucus hypersecretion and emphysema have been recognized for centuries. At the same time, we have struggled to define criteria that would help us identify patients at an early stage, prior to the development of pulmonary function abnormality. The concept of GOLD 0 was introduced in the hopes that symptoms would help to identify those at greatest risk for progression. While symptoms are a risk factor, in particular chronic bronchitis, the term was abandoned as the majority of individuals at risk who progress to COPD do not have symptoms. Since then, the related terms pre-COPD and early COPD have been introduced. They are similar in that the term pre-COPD identifies individuals based on symptoms, physiologic, or radiographic abnormality that do not meet criteria for COPD but are clearly at risk. The term early COPD extends that concept further, focusing on individuals who have early physiologic or radiographic abnormality but at the same time are young, thereby excluding those with late mild disease who may be less likely to progress. Whereas individuals with early COPD are now being recruited for observational studies, we are still challenged with determining the best way to identify patients at risk who should undergo additional testing as well as developing specific therapies for patients with early-stage disease.

41 cases of chronic obstructive pulmonary disease caused by occupational irritating chemicals

Objective: To analyze the case characteristics of Chronic obstructive pulmonary disease caused by occupational irritant chemicals (OI-COPD). To provide basis for revising its diagnostic criteria. Methods: From June to December 2021, we investigated the information of OI-COPD patients confirmed by Shandong Institute of Occupational Health and Prevention of Occupational Diseases, Guangxi Zhuang Autonomous Region Institute of Occupational Disease Prevention and Control, Qingdao Central Hospital affiliated to Qingdao University and other diagnostic institutions in the past five years, a total of 41 cases. The basic information of OI-COPD cases, occupational risk factors exposure information, medical history, smoking history and clinical symptoms were analyzed retrospectively. The measurement data were tested for normal distribution, which was described by x±s, and compared between groups by t test; Those who do not conform to the normal distribution are described by the median [M (Q(1), Q(3)) ] and analyzed by nonparametric test; The counting data were expressed in frequency and rate (% ), and the comparison between groups was tested. Results: Of the 41 cases, 33 were male and 8 were female. The age of the patient diagnosed with OI-COPD was (49.5±10.3) years old, and the minimum age was 30 years old; Among them, 8 patients had a definite long-term smoking history (more than 5 years) ; The exposure duration of occupational risk factors was (18.6±10.3) years, of which 3 patients had exposure duration of less than 5 years; The occupational risk factors leading to OI-COPD include acids and acid-forming compounds, bases, aldehydes, nitrogen oxides, chlorine and its compounds, etc. The exposure level of occupational risk factors is related to the degree of COPD airflow restriction (χ(2)=6.17, P <0.05). 18 patients with diagnosis age <50 years old were diagnosed as early-onset COPD. The incidence of respiratory symptoms in the early diagnosis COPD group was lower than that in the non-early diagnosis COPD group, and the FEV1% pred was significantly higher than that in the non-early diagnosis COPD group. The difference was statistically significant (P<0.01 ) . Conclusion: The exposure level of occupational risk factors may be the risk factor affecting the degree of COPD airflow restriction. With the increase of the exposure level of COPD patients, the proportion of respiratory symptoms will also increase accordingly.

The Lognormal Lung: A new approach to quantifying lung inhomogeneity in COPD.

Early diagnosis and disease phenotyping in COPD are currently limited by the use of spirometry, which may remain normal despite significant small-airways disease and which may not fully capture a patient's underlying pathophysiology. In this study we explored the use of a new non-invasive technique that assesses gas-exchange inhomogeneity in patients with COPD of varying disease severity (according to GOLD Stage), compared with age-matched healthy controls. The technique, which combines highly accurate measurement of respiratory gas exchange using a bespoke molecular flow sensor and a mechanistic mathematical model of the lung, provides new indices of lung function: the parameters σCL, σCd, and σVD represent the standard deviations of distributions for alveolar compliance, anatomical deadspace and vascular conductance relative to lung volume, respectively. It also provides parameter estimates for total anatomical deadspace and functional residual capacity (FRC). We demonstrate that these parameters are robust and sensitive, and that they can distinguish between healthy individuals and those with mild-moderate COPD (stage 1-2), as well as distinguish between mild-moderate COPD (stage 1-2) and more severe (stage 3-4) COPD. In particular, σCL, a measure of unevenness in lung inflation/deflation, could represent a more sensitive non-invasive marker of early or mild COPD. In addition, by providing a multi-dimensional assessment of lung physiology, this technique may also give insight into the underlying pathophysiological phenotype for individual patients. These preliminary results warrant further investigation in larger clinical research studies, including interventional trials.

The Dietary Inflammatory Index and Early COPD: Results from the National Health and Nutrition Examination Survey.

We examined 3962 people aged 20 to 49 years who had information on spirometry testing and underwent a 24 h dietary recall interview from the 2007–2012 National Health and Nutrition Examination Survey (NHANES) and used multivariable logistic regression to evaluate associations between Dietary Inflammatory Index (DII, a pro-inflammatory diet) and early COPD and lung function. The overall prevalence of early COPD was 5.05%. Higher DII was associated with increased odds of early COPD (quartile 4 vs. 1, the OR = 1.657, 95% CI = 1.100–2.496, p = 0.0156). In a full-adjusted model, each unit of increase in DII score was associated with a 90.3% increase in the risk of early COPD. Higher DII is significantly associated with lower FEV1 and FVC among individuals with early COPD, each unit increment in the DII was significantly associated with 0.43 L–0.58 L decrements in FEV1 (β = –0.43, 95% CI = −0.74, −0.12) and FVC (β = −0.58, 95% CI = −1.01, −0.16). These findings demonstrate that higher consumption of a pro-inflammatory diet may contribute to an increased risk of early COPD and lower lung function, and further support dietary interventions as part of a healthy lifestyle in order to preserve lung function and prevent or improve COPD.

Reversal of NADPH Oxidase-Dependent Early Oxidative and Inflammatory Responses in Chronic Obstructive Pulmonary Disease by Puerarin.

In the present study, we investigated effects of Puerarin on the early oxidative and inflammatory responses in the lung triggered by acute cigarette smoking (ACS). C57BL/6 mice were exposed to ACS for 1 hr in the presence or absence of Puerarin and harvested at 2, 6, and 24 hours. ACS induced significant increases in superoxide production in mouse lungs at 2 and 6 hours; and superoxide production was also elevated in a time and concentration dependent manner in cigarette smoke extract (CSE) stimulated human small airway epithelial cells (HSAECs), which was dose-dependently abrogated by Puerarin. ACS exposure upregulated NOX1, NOX2, and NOX4 protein expression in mouse lungs. Likewise, NOX1 and NOX4 were upregulated in CSE-stimulated HSAECs. These responses were significantly or completely attenuated by Puerarin. ACS induced significant infiltrations of neutrophils and macrophages in mouse lung parenchyma and BAL fluid, which were completely or significantly abrogated by Puerarin, so was the activation of the NF-кB pathway and the upregulation in inflammatory mediators including TNF-α, KC (murine homolog of IL-8), COX-2, IL-6 and MCP-1. Nuclear translocation of p65, IL-8 secretion, and upregulation of COX-2 in CSE stimulated HSAECs were also markedly attenuated by Puerarin. Moreover, ACS or CSE stimulated upregulation in reactive oxygen species (ROS) production and expression of inflammatory mediators were alleviated by ROS scavenger TEMPO in vivo and vitro, with no synergy combining with Puerarin, indicating that the effects of Puerarin are redox-sensitive following activation of NOX. In summary, our data for the first time demonstrate that Puerarin robustly attenuates NOX isoform-dependent ROS production and inflammatory activation in ACS exposed mice and CSE treated HSAECs, indicating that Puerarin might be used as a robust therapeutic agent for early or early stage COPD.

Early COPD Risk Decision for Adults Aged From 40 to 79 Years Based on Lung Radiomics Features.

BackgroundChronic obstructive pulmonary disease (COPD), a preventable lung disease, has the highest prevalence in the elderly and deserves special consideration regarding earlier warnings in this fragile population. The impact of age on COPD is well known, but the COPD risk of the aging process in the lungs remains unclear. Therefore, it is necessary to understand the COPD risk of the aging process in the lungs, providing an early COPD risk decision for adults.MethodsCOPD risk is evaluated for adults to make an early COPD risk decision from the perspective of lung radiomics features. First, the subjects are divided into four groups according to the COPD stages. Their ages are divided into eight equal age intervals in each group. Second, four survival Cox models are established based on the lung radiomics features to evaluate the risk probability from COPD stage 0 to suffering COPD and COPD stages. Finally, four risk ranks are defined by equally dividing the COPD risk probability from 0 to 1. Subsequently, the COPD risk at different stages is evaluated with varying age intervals to provide an early COPD risk decision.ResultsThe evaluation metrics area under the curve (AUC)/C index of four survival Cox models are 0.87/0.94, 0.84/0.83, 0.94/0.89, and 0.97/0.86, respectively, showing the effectiveness of the models. The risk rank levels up every 5 years for the subjects who had suffered COPD after 60. For the subjects with COPD stage 0, the risk rank of suffering COPD stage I levels up every 5 years after the age of 65 years, and the risk rank of suffering COPD stages II and III & IV levels up every 5 years after the age of 70 years.ConclusionOnce the age is above 60 years, the patients with COPD need to take action to prevent the progress and deterioration of COPD. Once the age is above 65 years, the patients with COPD stage 0 need to take precautions against COPD.

Impact of the UK lockdown on people at risk of COPD.

Impact of the UK lockdown on early COPD https://bit.ly/3laMsmi

Early Detection of COPD: An Opportunistic Case Finding Study in Smokers and Ex-Smokers Visiting a Medical Centre.

BackgroundDifferent case finding approaches have been used to identify early COPD. The objective of this study was to assess the feasibility and the yield of opportunistic early COPD case finding in visitors to a large medical centre.Patients and MethodsFrom May 2014 to June 2017, we consecutively recruited adults aged ≥ 18 years visiting the Shaare Zedek Medical Center, in Jerusalem. Our 3-step intervention included: a) pre-screening for symptoms with the 5-item “Could it be COPD?” questionnaire (score= 0–5 pts); b) pre-BD spirometry; and c) referral to a caregiver. Airflow obstruction was defined by a FEV1/FVC < 0.7. Spirometry results were used as an incentive to promote smoking cessation and quit rates were verified by phone survey 3 months after the intervention.ResultsA total of 1001 subjects (956 smokers; 45 ex-smokers) were recruited. Mean (SD) age was 48.3 years (13.5). Airflow obstruction was detected in 180 (18%) subjects of whom 142 (78.9%) were unaware of it, including 27 subjects with severe (50% ≥ FEV1 ≤ 30% predicted) (n=25) or very severe (FEV1 < 30% predicted) (n=2) obstruction. Multiple logistic regression analysis found that age, BMI, cigarette smoking (p.y.) and a “Could it be COPD?” questionnaire score ≥ 3 points correctly classified 83.3% of cases of airflow obstruction. At follow-up, 54.5% of participants reported smoking as usual, 30.9% reduced smoking [mean (SD) = 10.1 ± 7.8 cigarettes/day], 7.4% increased smoking [mean (SD) = 9.2 ± 6.3 cigarettes/day] and 7.2% claimed smoking cessation. Among obstructed subjects, 38.7% had visited a physician because of COPD, while 20.7% were taking a new respiratory medication.ConclusionEarly COPD case finding was feasible and effective in identifying undiagnosed airflow obstruction among visitors to a medical centre. Smoking cessation counselling based on spirometry promoted a small but clinically meaningful cessation rate.

Effects of Donor Smoking History on Early Post-Transplant Lung Function Measured by Oscillometry

<h3>Purpose</h3> Oscillometry (Osc) is a non-invasive test of respiratory impedance that is sensitive to small airways, a region not well characterized by conventional pulmonary function tests (PFT). It has been shown to detect early COPD prior to changes in PFT. We posit that Osc could identify small airway obstruction post-lung transplant (LTx) and discriminate between lungs from smoking vs non-smoking donors. <h3>Methods</h3> Double LTx recipients who consented were prospectively tested with Osc and PFT during post-LTx follow-up. Osc was conducted according to ERS criteria. Mann-Whitney U test was used to compare Osc and PFT results of recipients of non-smoking vs. smoking donor lungs. <h3>Results</h3> From December 2017 to December 2019, 268 patients were enrolled. 106 received lungs from non- smokers and 147 from smokers, with 36 heavy (> 20 pack years) smokers. We excluded 6 patients with no donor smoking history and 9 who did not undergo any testing.No differences were observed between smoking and non-smoking donor groups overall. However, in the subgroup which received Ltx from heavy smokers, Osc identified small airway obstruction at 8 weeks post-LTx. The main Osc parameters of small airway obstruction, R5-R19, AX (area of reactance) and X5 (reactance at 5 Hz) were significantly different between the 2 groups. In contrast, no differences were observed in the FEV1/FVC or the % predicted FEV1 (Figure 1). The difference in R5-R19 persisted at 3 months but not observed for AX and X5. <h3>Conclusion</h3> Recipients of lungs from donors with heavy smoking history had evidence of small airway obstruction detected by Osc which was not reflected in traditional PFT parameters. This was not observed in donors with a < 20 pack year smoking history, suggesting that moderate smoking is unlikely to affect posttransplant lung function. Longer follow-up is needed to determine whether the observed differences persist over time and lead to graft dysfunction.

Early diagnosis of COPD: myth or a true perspective.

The early stages of COPD have recently become a hot topic as many new risk factors have been proposed, but substantial knowledge gaps remain in explaining the natural history of the disease. If we are to modify the outcomes of COPD, early detection needs to play a critical role. However, we need to sort out the barriers to early detection and have a better understanding of the definition of COPD and its diagnosis and therapeutic strategies to identify and treat patients with COPD before structural changes progress. In this review, we aim to clarify the differences between early COPD, mild COPD and early detection of COPD, with an emphasis on the clinical burden and how different outcomes (quality of life, exacerbation, cost and mortality) are modified depending on which definition is used. We will summarise the evidence for the new multidimensional diagnostic approaches to detecting early pathophysiologic changes that potentially allow for future studies on COPD management strategies to halt or prevent disease development.

Diagnosis and Treatment of Early Chronic Obstructive Lung Disease (COPD).

Chronic obstructive lung disease (COPD) is responsible for substantial rates of mortality and economic burden, and is one of the most important public-health concerns. As the disease characteristics include irreversible airway obstruction and progressive lung function decline, there has been a great deal of interest in detection at the early stages of COPD during the “at risk” or undiagnosed preclinical stage to prevent the disease from progressing to the overt stage. Previous studies have used various definitions of early COPD, and the term mild COPD has also often been used. There has been a great deal of recent effort to establish a definition of early COPD, but comprehensive evaluation is still required, including identification of risk factors, various physiological and radiological tests, and clinical manifestations for diagnosis of early COPD, considering the heterogeneity of the disease. The treatment of early COPD should be considered from the perspective of prevention of disease progression and management of clinical deterioration. There has been a lack of studies on this topic as the definition of early COPD has been proposed only recently, and therefore further clinical studies are needed.

A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis.MethodsWe conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach.ResultsThere were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10− 4 in the discovery and OR = 1.30, P = 1.8 × 10− 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52–2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94–1.20).ConclusionsOur study shows that circulating blood GlycA is a biomarker of early COPD pathology.

Design of the Redefining Therapy in Early COPD Study.

Redefining Therapy in Early COPD (RETHINC) is a 12-week multicenter, randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily in symptomatic current and former smokers with respiratory symptoms as defined by COPD Assessment Test (CAT) score ≥ 10 despite preserved spirometry defined by post-bronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio ≥ 0.70. Recruitment began in July 2017 with the goal of enrolling 580 participants. The baseline examination includes spirometry (with slow and forced maneuvers) and symptom questionnaires. A follow-up phone call at 4 weeks assesses symptoms and safety. The second and final visit at week 12 includes spirometry before and after study drug (hourly over 3 hours) and follow-up symptom questionnaires. The primary endpoint is the proportion of individuals who experience a 4-unit improvement in St George's Respiratory Questionnaire (SGRQ) score at 12 weeks without treatment failure, defined as an increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilators, corticosteroids or antibiotics. Key secondary endpoints include the proportion of individuals with a 2-unit improvement in the CAT score; 1-unit improvement in the Baseline Dyspnea Index (BDI) and Transition Dyspnea Index (TDI), both a 4-unit improvement in SGRQ and a 1-unit improvement in BDI/TDI; and mean change in SGRQ, CAT and BDI/TDI. Other secondary endpoints include area under the curve 0-3 hours for FEV1 after study drug, change from baseline in trough inspiratory capacity, forced expiratory flow 25%-75% of FVC (FEF25-75) iso-volume FEF25-75 and mean change in symptoms and rescue medication use based on daily diary. We anticipate results to be available in 2021. This paper describes the RETHINC study and explains the rationale behind it.